Non-invasive optical measurement of cerebral critical closing pressure in pediatric hydrocephalus

Hydrocephalus is a common disorder of cerebral spinal fluid (CSF) physiology that results in elevated intracranial pressure (ICP) and progressive expansion of cerebral ventricles.1 It affects 1-2 of every 1000 live births, making it the most common disease treated by pediatric neurosurgeons in the US.1 In roughly half of infants with hydrocephalus, ventricular expansion requires surgical intervention whereby a shunt is placed in the ventricles to divert CSF and relieve elevated ICP. Although timely treatment of elevated ICP is important for brain tissue viability, its implementation is hindered by the lack of tools for non-invasive ICP measurement. This study aims to validate non-invasive intracranial pressure (ICP) assessment with the near-infrared diffuse correlation spectroscopy (DCS) technique in infants with hydrocephalus. DCS employs near-infrared light to measure local, microvascular cerebral blood flow (CBF) continuously at the bedside. In addition to CBF, a novel approach for measurement of cerebral critical closing pressure (CrCP) based on DCS measurements of pulsatile CBF in arterioles was recently demonstrated.2-4 CrCP, which depends on ICP, defines the arterial blood pressure at which CBF approaches zero. Intraoperative non-invasive CrCP measurements with DCS on the prefrontal cortex were performed concurrently with invasive ICP measurements in 9 infants with hydrocephalus at the Children’s Hospital of Philadelphia. Invasive ICP was measured during surgical shunt placement. Please click Additional Files below to see the full abstract

Parental Factors Associated With the Decision to Participate in a Neonatal Clinical Trial

Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation. Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial. Design, setting, and participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020. Exposure: Parental choice of enrollment in neonatal clinical trial. Main outcomes and measures: Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child's medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant's illness, (3) study comprehension, and (4) trust in clinicians and researchers. Results: Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%]; P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%]; P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant's medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment. Conclusions and relevance: In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities

Oxygen Sensing Neurons and Neuropeptides Regulate Survival after Anoxia in Developing <i>C. elegans</i>

<div><p>Hypoxic brain injury remains a major source of neurodevelopmental impairment for both term and preterm infants. The perinatal period is a time of rapid transition in oxygen environments and developmental resetting of oxygen sensing. The relationship between neural oxygen sensing ability and hypoxic injury has not been studied. The oxygen sensing circuitry in the model organism <i>C. elegans</i> is well understood. We leveraged this information to investigate the effects of impairments in oxygen sensing on survival after anoxia. There was a significant survival advantage in developing worms specifically unable to sense oxygen shifts below their preferred physiologic range via genetic ablation of BAG neurons, which appear important for conferring sensitivity to anoxia. Oxygen sensing that is mediated through guanylate cyclases (<i>gcy-31, 33, 35</i>) is unlikely to be involved in conferring this sensitivity. Additionally, animals unable to process or elaborate neuropeptides displayed a survival advantage after anoxia. Based on these data, we hypothesized that elaboration of neuropeptides by BAG neurons sensitized animals to anoxia, but further experiments indicate that this is unlikely to be true. Instead, it seems that neuropeptides and signaling from oxygen sensing neurons operate through independent mechanisms, each conferring sensitivity to anoxia in wild type animals.</p></div

Worms Appear Stunned after Anoxia.

<p>Photographs of worms before (A) and after (B) anoxia. Prior to insult, animals are freely moving and their appearance has a characteristic sinusoidal shape as their bodies bend with locomotion. After anoxia, they enter suspended animation (“stunned”) and do not move. They appear either arched or as rods. This is a reversible state, and surviving animals will begin moving within 24 hours after being removed from the anoxia chamber.</p

Adapted from [9].

<p>Adapted from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101102#pone.0101102-Zimmer1" target="_blank">[9]</a>.</p

Anoxic Survival is Not Dependent on Guanylate Cyclase Activity in Oxygen Sensing Neurons.

<p>Mutant strains with null alleles in guanylate cyclases (GC) responsible for transducing oxygen shifts into neural signals (<i>gcy-31, gcy-35, gcy-33</i>) did not show significant survival differences compared to wild type (<i>gcy-31</i> vs N2, <i>p</i> = 0.15; <i>gcy-35</i> vs N2, <i>p</i> = 0.96; <i>gcy-33</i> vs N2, <i>p</i> = 0.57), suggesting that the observed survival benefit in the BAG (−) animals was not dependent on GC activity (A). Mutants with null alleles in multiple GCs also did not show significant survival benefit (<i>gcy-35; gcy-33; gcy-31</i> vs N2, <i>p</i> = 0.52; <i>gcy-33; gcy-31</i> vs N2, <i>p</i> = 0.47), demonstrating that compensated activity does not explain lack of effect seen in single mutants (B). Error bars represent standard deviation. All data were analyzed using a two-tailed paired t-test. The number of animals evaluated and number of trials conducted is listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101102#pone-0101102-t001" target="_blank"><b>Table 1</b></a>.</p

Impaired Neuropeptide Processing and Secretion Improves Survival after Anoxia and Susceptibliity is not Restored with BAG-Specific Neuropeptide Processing Rescue.

<p>Survival after anoxia in worm strains with <i>egl-3</i> null alleles (A & B), which impair neuropeptide processing. Black bars depict survival rates of co-bagged wild type (N2) animals and are compared to survival rates in mutant strains (light gray bars) labeled on x-axis. Survival is signficantly improved in <i>egl-</i>3 animals after anoxia (<i>egl-3(gk238)</i> vs N2, 84.9% vs 56.8%, <i>p</i> = 0.0003; <i>egl-3(ok979)</i> vs N2, 83.7% vs 54.4%, <i>p</i> = 0.0004), suggesting a role for neuropeptide signaling in creating anoxic vulnerability. Furthermore, inability to secrete neuropeptides via mutation of the docking protein UNC-31 also demonstrated significant survival advantage (<i>unc-31</i> vs N2, 90.3% vs 41%, <i>p</i> = 0.0034) (C). In a third <i>egl-3</i> null background, <i>egl-3(n150)</i>, there is also a survival benefit and when rescue under a BAG-specific promoter, <i>flp-17,</i> is performed via an extra-chromosomal array, there is no restoration of anoxic sensitivity (<i>egl-3(n150)</i> vs N2, 61.7% vs 38.9%, p = 0.03; <i>egl-3(n150); kyEx4050</i> vs N2, 61.5% vs 36%, <i>p</i> = 0.02) (D). Note that <i>egl-3(n150)</i> is a temperature-sensitive allele and the experiments depicted in D were conducted at 25 degrees Celsius for 24 hours. Error bars represent standard deviation. All data were analyzed using a two-tailed paired t-test. The numbers of animals trials conducted are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101102#pone-0101102-t001" target="_blank"><b>Table 1</b></a>.</p

A list of the strains of worms used in this study, the genotype for each strain, and a brief description of functional impairments.

<p>The column indicating #N2 controls indicates the number of N2 animals that served as matched controls for each survival experiment. The #Animals Evaluated indicates the number of animals for each strain that were subjected to anoxia for survival determination. The #Trials indicates the number of independent experiments that formed the basis of survival estimates for each strain. The final column of the table indicates the figure where the survival data appear.</p

Wild Type (N2) Survival After Anoxia of Varying Duration.

<p>This figure shows the survival of wild type (N2) worms after varied periods of anoxia. Survival was evaluated after the following anoxia times: 24 h (2 trials, n = 202), 30 h (2 trials, n = 192), 40 h (11 trials, n = 775), 48 h (9 trials, n = 651) and 70 hours (2 trials, n = 162). Error bars represent standard deviation.</p

Impaired Sensing of Oxygen Downshifts Confers Survival Benefit that is Specific to Anoxic Stress.

<p>This figure shows survival results after 40–48 hours of anoxia in worms strains mutated in their ability to sense oxygen shifts. Co-bagged wild type animals (N2) were included as a control to compare mutant strain survival. The graphs depict mean survival in each strain labeled on the x-axis (light gray bars) compared to paired wild type (N2) survival (black bars). In worms with genetic manipulation that eliminates the BAG neuron, which senses oxygen shifts below the physiologic range (BAG −), there was a significant survival advantage compared to controls (67.2% vs 44.5%, <i>p</i> = 0.02). This was not seen in URX/AQR/PQR (−), which were genetically manipulated in their ability to sense oxygen shifts above the physiologic range (40.3% vs 45.8%, <i>p</i> = 0.46) (A). Lifespan (B) and mean survival (C) after heat shock lifespan was not extended in BAG (−) animals compared to N2 controls and URX/AQR/PQR (−) (<i>F</i>_(2,6) = 1.000; <i>p = </i>0.42). Error bars represent standard deviation. Comparative anoxia survival data were analyzed using a two-tailed paired t-test. The mean lifespan was analyzed using one-way ANOVA. The number of animals evaluated and number of trials conducted is listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101102#pone-0101102-t001" target="_blank"><b>Table 1</b></a>.</p